The proposed research will seek evidence for linkage between the locus for Huntington Disease (HD) and a wide variety of polymorphic markers. A model for linkage and genetic analysis of disorders with age dependent penetrance will be developed. Blood, urine and saliva samples will be obtained from families with two or more generations with HD. The blood will be typed for all the common blood group markers and serum enzymes, haptoglobin, Gm and Km allotypes, and saliva will be typed for secretor status, salivary amylase and parotid saliva for acid basic and proline rich proteins (Pa, Pb, Pr, Db) and urine for urinary amylase and pepsinogen. All individual samples will be stored so that new markers which will be developed can be typed for. The data will be analyzed using the program LIPED, based on the Elston-Stewart Algorithm which analyzes whole families. Due to this methodology, accurate classification of individuals at risk for HD is no longer essential but the probability of having inherited the HD gene, given that the individual is normal at a certain age, must be calculated. The distribution of age of onset that best describes the data will be determined together with correlation of onset age within families and incorporated into the analyses to assign accurate probabilities for at-risk individuals of having inherited the HD gene. Tests for linkage heterogeneity will be performed and the results correlated with clinical manifestations of the disorder. All existing HD families will be recontacted to determine the affected status of "at risk" members. We will also attempt to confirm the reported significant increae of the cholinesterase variants Ef or 1 and in C5 ion patients with HD and examine their segregation in HD sibships.